US4481189A - Process for preparing sterilized plasma and plasma derivatives - Google Patents

Process for preparing sterilized plasma and plasma derivatives Download PDF

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Publication number
US4481189A
US4481189A US06/368,250 US36825082A US4481189A US 4481189 A US4481189 A US 4481189A US 36825082 A US36825082 A US 36825082A US 4481189 A US4481189 A US 4481189A
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plasma
ether
factor viii
process according
virus
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US06/368,250
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Alfred M. Prince
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New York Blood Center Inc
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New York Blood Center Inc
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Application filed by New York Blood Center Inc filed Critical New York Blood Center Inc
Priority to US06/368,250 priority Critical patent/US4481189A/en
Assigned to NEW YORK BLOOD CENTER INC. reassignment NEW YORK BLOOD CENTER INC. ASSIGNMENT OF ASSIGNORS INTEREST. Assignors: PRINCE, ALFRED M.
Priority to EP83103049A priority patent/EP0099445B2/en
Priority to DE8383103049T priority patent/DE3382042D1/de
Priority to AT83103049T priority patent/ATE58835T1/de
Priority to ZA832239A priority patent/ZA832239B/xx
Priority to FI831146A priority patent/FI80211C/fi
Priority to DK162983A priority patent/DK164537C/da
Priority to ES521431A priority patent/ES521431A0/es
Priority to NO831304A priority patent/NO163514C/no
Priority to NZ203878A priority patent/NZ203878A/en
Priority to AU13462/83A priority patent/AU561900B2/en
Priority to JP58064638A priority patent/JPH0660105B2/ja
Priority to CA000425864A priority patent/CA1207229A/en
Priority to US06/581,528 priority patent/US4591505A/en
Publication of US4481189A publication Critical patent/US4481189A/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2/00—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor
    • A61L2/0005—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor for pharmaceuticals, biologicals or living parts
    • A61L2/0011—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor for pharmaceuticals, biologicals or living parts using physical methods
    • A61L2/0029—Radiation
    • A61L2/0035—Gamma radiation
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/14—Quaternary ammonium compounds, e.g. edrophonium, choline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/14—Blood; Artificial blood
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/14—Blood; Artificial blood
    • A61K35/16—Blood plasma; Blood serum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2/00—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor
    • A61L2/0005—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor for pharmaceuticals, biologicals or living parts
    • A61L2/0082—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor for pharmaceuticals, biologicals or living parts using chemical substances
    • A61L2/0088—Liquid substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2/00—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor
    • A61L2/16—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor using chemical substances
    • A61L2/18—Liquid substances or solutions comprising solids or dissolved gases
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/745—Blood coagulation or fibrinolysis factors
    • C07K14/755—Factors VIII, e.g. factor VIII C (AHF), factor VIII Ag (VWF)

Definitions

  • This invention relates to mammalian blood plasma. More especially, this invention relates to the inactivation of hepatitis B or non-A, non-B viruses in human blood plasma and to the resultant products. In particular, this invention relates to the sterilization of blood plasma to render it virtually free of active hepatitis viruses, such that the valuable proteins present therein, such as factor VIII are not appreciably denatured.
  • HBV hepatitus B virus
  • BPL ⁇ -propiolactone
  • factor VIII is inactivated or denatured to the extent of 50-90% or more of the factor VIII present in the untreated plasma. Because of the denaturing effects of these virus inactivating agents, it is necessary in the preparation of derivatives for administration to patients to concentrate large quantities of plasma so that the material to be administered to the patient once again has a sufficient concentration of the undenatured protein for effective therapeutic treatment. This concentration, however, does not affect reduction of the amount of denatured protein. As a result, the patient not only receives the undenatured protein but a quantity of denatured protein often many times that of the undenatured protein.
  • Factor VIII is denatured to a larger extent that the other valuable proteins present in blood plasma.
  • BPL/UV inactivation procedure discussed above has not so far been adopted in the United States for numerous reasons, one of which lies in the fact that many researchers believe that BPL is itself deleterious since it cannot be removed completely following the inactivation and thus may remain in plasma and plasma derivatives in more than negligible amounts. BPL has been shown to be carcinogenic in animals.
  • a further advantage of the proposed procedures is the fact that plasma, or plasma protein solutions so treated become totally clear and transparent as a result of the removal of plasma lipids. Furthermore, the clarity is maintained indefinitely on storage at 4° C. This has important advantages over untreated plasma or plasma protein solutions in that:
  • both hepatitis B and non-A, non-B viruses are substantially inactivated and that the weight percent of denatured factor VIII in the plasma is less than 30%-50% based upon the combined amount of denatured and undenatured factor VIII therein.
  • Prior to treatment pooled human blood plasma usually has an active hepatitis B virus content between 10 1 virus particles per milliliter and 10 3 virus particles per milliliter as well as substantial (10 1 -10 2 ) amounts of non-A, non-B virus particles. After treatment, no living virus particles remain.
  • a mammalian blood plasma characterized by the presence of factor VIII wherein the percent by weight of denatured factor VIII to the sum of undenatured factor VIII and denatured factor VIII is less than 30%-50% said plasma containing no hepatitis B or non-A, non-B viruses.
  • the mammalian blood plasma contains less than 50% by weight of denatured factor VIII based upon the sum of denatured and undenatured factor VIII present therein. More especially, it is preferred that this value be less than 15 and still more especially, less than 10% by weight.
  • denatured factor VIII By suitable processing, one can reduce the weight percent of denatured factor VIII to less than 5%, especially less than 3%, more especially less than 2% by weight based upon the combined weight of denatured and undenatured factor VIII.
  • the inactivated hepatitis virus is inactivated by treatment with the specifically contemplated inactivating agents described herein, and is not inactivated because of inclusion in the plasma of antibodies which bind with the hepatitis viruses and form immune complexes; although this may occur also.
  • blood plasma of the invention can be characterized by containing a residual amount of nonionic detergent, ether or alcohol but such nonionic detergent, ether or alcohol is present in a concentration of less than 1%, preferably less than 0.001%.
  • plasmas obtained from donors can be pooled without special precautions to insure that plasma containing active hepatitis B virus is not added to the pool. This facilitates the processing of the plasma and enables elimination of several steps, including early testing of each pint of blood received from the donor. It permits processing of large quantities of plasma with attendant savings in costs.
  • the treating agent preferably comprises 0.1 to 10% by weight detergent based upon the volume of plasma or plasma derivatives to be treated.
  • a treating agent comprising a mixture of detergent and ether where the detergent is present in the composition in an amount of 0.1 to 10%, preferably 0.1 to 1.0%, based upon the volume of plasma or plasma derivative to be treated.
  • the ether, or alcohol can be added in an amount of 5 to 50%, preferably 20 to 40% by weight, based on the volume of plasma or plasma derivatives to be treated.
  • the pH of the inactivating agent solution, dispersion, or suspension is from 6.0 to 8.0.
  • ethers for use inactivation in accordance with the invention are those having the formula
  • R 1 and R 2 are independently C 1 -C 18 alkyl or alkenyl which can contain an O or S atom in the chain, preferably C 1 -C 8 alkyl or alkenyl.
  • ethers are dimethyl ether, diethyl ether, ethyl propyl ether, methyl-butyl ether, methyl isopropyl ether and methyl isobutyl ether.
  • R 3 is a C 1 to C 18 alkyl or alkenyl radical which can contain 1 or more oxygen or sulphur atoms in the chain and which can be substituted by one or more hydroxyl groups.
  • Especially contemplated alcohols are those where the alkyl or alkenyl group is between 1 and 8 carbon atoms.
  • Particularly contemplated alcohols include methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol, n-pentanol and isopentanols.
  • compounds such as ethylene glycol, 1,2-propylene glycol, 1,3-propane diol, 1,4-butanediol, 1,3-butanediol, 2-hydroxy isobutanol (2-methyl, 1,2-dihydroxypropane).
  • Contemplated nonionic detergents include those which disperse at the prevailing temperature up to 0.1% by weight fat in an aqueous solution containing 0.1% by weight fat when 1 gram per 100 ml of detergent is introduced therein.
  • detergents which include polyoxyethylene derivatives of fatty acids, partial esters of sorbitol anhydrides, for example, those products known commercially as Tween 80 and Tween 20 nonionic oil soluble water soluble detergent such as that sold commercially under the trademark "Triton X 100".
  • sodium deoxycholate as well as the "Zwittergents” which are synthetic zwitterionic detergents known as "sulfobetaines" such as N-dodecyl -N,N-dimethyl-2-ammonio-1-ethane sulphonate and its congeners or nonionic detergents such as octyl-beta-D-glucopyranoside.
  • sulfobetaines such as N-dodecyl -N,N-dimethyl-2-ammonio-1-ethane sulphonate and its congeners or nonionic detergents such as octyl-beta-D-glucopyranoside.
  • non-ionic detergents are those having about 15 to about 35, preferably about 18 to 33, oxyethylene units in the molecule, especially in the presence of a mercaptan reducing agent, such as, for example, mercaptoethanol, dithiothreitol, dithioerythritol, and dithiooctanoic acid.
  • a mercaptan reducing agent such as, for example, mercaptoethanol, dithiothreitol, dithioerythritol, and dithiooctanoic acid.
  • Suitable nonionic surfactants are oxyethylated alkyl phenols, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene acids, polyoxyethylene alcohols, polyoxyethylene oils and polyoxyethylene oxypropylene fatty acids.
  • Treatment of plasma with the inactivating agent is effected at a temperature between -5° C. and 50° C., preferably between 1° and 4° C. for at least 1 minute, preferably at least 16 hours and generally 16 to 24 hours.
  • the treatment is normally effective at atmospheric pressure although subatmospheric and superatmospheric pressures can also be employed.
  • the virus inactivating agent is removed although such is not necessary in all instances, depending upon the nature of the virus inactivating agent and the intended further processing of the plasma.
  • the plasma is generally subjected to a temperature of 4 to 37° C. with a slight vacuum imposed to draw off residual ether.
  • Preferably means are provided to spread the plasma as a thin film to insure maximum contact and removal of the ether.
  • Other methods for removal of ether in activating agents include;
  • any ether present is initially removed prior to removal of any detergent.
  • the ether may be recovered for reuse by the use of suitable distillation/condensor systems well known to the art.
  • Alcohol is normally removed together with detergent. If the detergent includes both alcohol and ether, the ether is normally removed before the alcohol.
  • blood plasma can be characterized by the relative amount of denatured factor VIII to the sum of denatured and undenatured factor VIII.
  • the weight percent of denatured factor VIII to the sum of denatured and undenatured factor VIII is less than 50%.
  • Detection of the amount of denatured factor VIII is determined by determining the ratio between factor VIII antigen (CAG.) content (a measure of factor VIII protein) and factor VIII activity(a measure of undenatured factor VIII.
  • the ratio: F VIII activity:CAG Antigen is ideally 1.0 when there is no denaturation, and should not be less than 0.5.
  • the method of the invention permits the pooling of human blood plasma and the treatment of the pooled human blood plasma in the form of such pooled plasma. It also permits the realization of blood products derivatives such as factor VIII gamma globulin, factor IX or the factor IX complex (factors II VII, IX X), fibrinogen and any other blood derivative including HBsAg used for the preparation of HBV vaccine, all of which contain no residual infective hepatitis viruses.
  • this invention further contemplates the separate components of pooled plasma where each of the components is characterized by:
  • New York Blood Center Standard HBV challenge virus (plasma 78-564 obtained from a chronic carrier of the virus) was diluted 1:10 with fresh normal (chimp 222) chimpanzee plasma lacking antibody to HBsAg. This dilution contains 10 7 .9 chimpanzee infectious doses (CID 50 ) per ml. Tween 80 was added to make a final concentration of 1% V/V, and then ethyl ether. (Malinckyodt, anaesthetic grade) was added to a final concentration of 20% V/V. The solution was well mixed by vortexing, and then held at 4° C. for 16 hours. Ether was then removed under vacuum, the solutions were centrifuged for 10 min.
  • the infective plasma was a 10 -1 dilution of HUTCHINSON STRAIN (7-12-77) Non-A, non-B virus received frozen in dry ice from Dr. Robert Purcell, head of the Hepatitis Laboratory, National Institute for Allergy & Infectious Diseases, N.I.H., Bethesda, Md.
  • This material produces non-A, non-B hepatitis in chimpanzees with an incubation period prior to ALT elevation of about 5-7 weeks.
  • This material has been found to have a titer of about 10 6 CID 50 /ml in chimpanzees, and about 10 8 ID 50 in marmosets (Feinstone, S. & Purcell R. H., Personal Communication).
  • the treated plasma which contained a 10 -2 dilution of the Hutchinson Plasma had an infective virus content of 10 4 -10 6 1D 50 /ml.
  • the process efficacy for inactivation of non-A, non-B virus estimated from this experiment is ⁇ 10 4 -10 6 i.e., at least 10,000-1,000,000 infective doses can be inactivated.
  • Lyoc® is a concentrate of factor VIII which is licensed for clinical use in the treatment of hemophilia. Lyoc is prepared without attempted sterilization of hepatitis viruses, and is thus probably uniformly infective to non-immune recipients. A sample of Lyoc was treated with Tween-80/ether, as described above to determine whether the contained factor VIII activity would be preserved.
  • the process of the invention is useful in the inactivation of other viruses present in blood such as: cytomegaloviruses, Epstein Barr viruses, lactic dehydrogenase viruses, herpes group viruses, rhabdoviruses, leukoviruses, myxoviruses, alphaviruses, Arboviruses (group B), paramyxo viruses, arenaviruses, coronaviruses.
  • viruses present in blood such as: cytomegaloviruses, Epstein Barr viruses, lactic dehydrogenase viruses, herpes group viruses, rhabdoviruses, leukoviruses, myxoviruses, alphaviruses, Arboviruses (group B), paramyxo viruses, arenaviruses, coronaviruses.

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US06/368,250 1982-04-14 1982-04-14 Process for preparing sterilized plasma and plasma derivatives Expired - Lifetime US4481189A (en)

Priority Applications (14)

Application Number Priority Date Filing Date Title
US06/368,250 US4481189A (en) 1982-04-14 1982-04-14 Process for preparing sterilized plasma and plasma derivatives
EP83103049A EP0099445B2 (en) 1982-04-14 1983-03-26 Sterilized plasma and plasma derivatives and process therefor
DE8383103049T DE3382042D1 (de) 1982-04-14 1983-03-26 Sterilisierte plasmanebenprodukte und verfahren zur herstellung.
AT83103049T ATE58835T1 (de) 1982-04-14 1983-03-26 Sterilisierte plasmanebenprodukte und verfahren zur herstellung.
ZA832239A ZA832239B (en) 1982-04-14 1983-03-29 Sterilized plasma and plasma derivatives and process therefor
FI831146A FI80211C (fi) 1982-04-14 1983-04-05 Metod foer inaktivering av hepatit b virusin plasma och plasmaderivat.
AU13462/83A AU561900B2 (en) 1982-04-14 1983-04-13 Sterilised plasma and plasma derivatives
ES521431A ES521431A0 (es) 1982-04-14 1983-04-13 Procedimiento para inactivar el virus de la hepatitis b.
DK162983A DK164537C (da) 1982-04-14 1983-04-13 Fremgangsmaade til inaktivering af hepatitis-b-virus eller non-a, non-b-hepatitisvirus i pattedyrsblodplasma eller pattedyrsplasmaproteinoploesninger
NO831304A NO163514C (no) 1982-04-14 1983-04-13 Fremgangsmaate for fremstilling av blodplasma.
NZ203878A NZ203878A (en) 1982-04-14 1983-04-13 Mammalian blood plasma free of living hepatitis b and non-a,non-b viruses
JP58064638A JPH0660105B2 (ja) 1982-04-14 1983-04-14 血漿中の肝炎ウイルスの不活性化方法
CA000425864A CA1207229A (en) 1982-04-14 1983-04-14 Sterilized plasma and plasma derivatives and process therefor
US06/581,528 US4591505A (en) 1982-04-14 1984-02-21 Process for inactivating hepatitis B virus

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US06/368,250 US4481189A (en) 1982-04-14 1982-04-14 Process for preparing sterilized plasma and plasma derivatives

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US06/581,528 Division US4591505A (en) 1982-04-14 1984-02-21 Process for inactivating hepatitis B virus

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US (1) US4481189A (es)
EP (1) EP0099445B2 (es)
JP (1) JPH0660105B2 (es)
AT (1) ATE58835T1 (es)
AU (1) AU561900B2 (es)
CA (1) CA1207229A (es)
DE (1) DE3382042D1 (es)
DK (1) DK164537C (es)
ES (1) ES521431A0 (es)
FI (1) FI80211C (es)
NO (1) NO163514C (es)
NZ (1) NZ203878A (es)
ZA (1) ZA832239B (es)

Cited By (70)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1985005273A1 (en) * 1984-05-18 1985-12-05 Purcell Robert H Utilizing a halohydrocarbon containing dissolved water to inactivate a lipid virus
US4581231A (en) * 1982-06-10 1986-04-08 The United States Of America As Represented By The Secretary Of Health And Human Services Inactivation of viruses containing essential lipids
US4613501A (en) * 1984-12-21 1986-09-23 New York Blood Center, Inc. Inactivation of viruses in labile blood derivatives
US4640834A (en) * 1984-03-09 1987-02-03 Immuno Aktiengesellschaft Fur Chemisch-Medizinische Produkte Method of inactivating reproducible filterable pathogens in blood products as well as a method of producing blood products
US4649192A (en) * 1985-05-30 1987-03-10 Smith Kline-Rit Method for the isolation and purification of hepatitis B surface antigen using polysorbate
WO1988001507A1 (en) * 1986-08-01 1988-03-10 Rubinstein Alan I A method to treat blood
US4740498A (en) * 1984-10-24 1988-04-26 Green Cross Corporation Fibronectin preparations
US4764369A (en) * 1983-07-14 1988-08-16 New York Blood Center Inc. Undenatured virus-free biologically active protein derivatives
US4789545A (en) * 1986-03-31 1988-12-06 New York Blood Center, Inc. Removal of lipid soluble process chemicals from biological materials by extraction with naturally occurring oils or synthetic substitutes thereof
US4803073A (en) * 1986-03-18 1989-02-07 Schwab & Co Ges.M.B.H. Process for the pasteurization of plasma proteins and plasma protein fractions
US4820805A (en) * 1983-07-14 1989-04-11 New York Blood Center, Inc. Undenatured virus-free trialkyl phosphate treated biologically active protein derivatives
US4841023A (en) * 1986-06-25 1989-06-20 New York Blood Center, Inc. Inactivation of viruses in labile protein-containing compositions using fatty acids
US4869826A (en) * 1987-09-01 1989-09-26 Process Biotechnology, Inc. Cellular adsorbents for removal of viral contaminants from blood and complex protein solutions
US4909940A (en) * 1987-12-30 1990-03-20 New York Blood Center, Inc. Extraction of process chemicals from labile biological mixtures with organic alcohols or with halogenated hydrocarbons
EP0366946A1 (en) 1988-10-07 1990-05-09 New York Blood Center, Inc. Removal of process chemicals from labile biological mixtures by hydrophobic interaction chromatography
US4939176A (en) * 1988-12-20 1990-07-03 Miles Inc. Viral inactivation process
US4944920A (en) * 1986-08-01 1990-07-31 University Of Southern California Novel method to treat blood
US4971760A (en) * 1986-03-10 1990-11-20 University Of Southern California Novel method for disinfecting red blood cells, blood platelets, blood plasma, and optical corneas and sclerae
US5011695A (en) * 1988-02-22 1991-04-30 Biotest Pharma Gmbh Sterilization of blood and its derivatives with vitamins
US5026686A (en) * 1989-02-01 1991-06-25 Washington University Antiviral peptides
US5071961A (en) * 1988-08-06 1991-12-10 Biotest Pharma Gmbh Method of enrichment of coagulation factors ii, vii, ix and x
US5185371A (en) * 1986-03-10 1993-02-09 University Of Southern California Method for disinfecting red blood cells
US5202246A (en) * 1989-08-16 1993-04-13 Armour Pharmaceutical Company Treatment of immobilized matrices for preparation of pharmaceutical and biological products with anti-microbial agents to remove pyrogen-producing organisms and pyrogens
US5211912A (en) * 1986-08-01 1993-05-18 University Of Southern California Method for disinfecting red blood cells, blood products, and corneas
US5281392A (en) * 1986-03-10 1994-01-25 Rubinstein Alan I Method for disinfecting red blood cells, blood products, and corneas
WO1995000631A1 (en) * 1993-06-23 1995-01-05 New York Blood Center, Inc. System for viral inactivation of blood
US5470954A (en) * 1987-03-31 1995-11-28 Baxter International Inc. Ultrapurification process for factor VIII
US5486293A (en) * 1994-03-21 1996-01-23 Hemasure, Inc. Removal of small exogenous molecules from biological fluids
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NO163514C (no) 1990-06-13
DK162983A (da) 1983-10-15
EP0099445A2 (en) 1984-02-01
DK164537B (da) 1992-07-13
ES8403722A1 (es) 1984-04-01
FI80211B (fi) 1990-01-31
ATE58835T1 (de) 1990-12-15
FI831146A0 (fi) 1983-04-05
JPS58222023A (ja) 1983-12-23
FI80211C (fi) 1990-05-10
DK162983D0 (da) 1983-04-13
ES521431A0 (es) 1984-04-01
ZA832239B (en) 1984-11-28
EP0099445B1 (en) 1990-12-05
DE3382042D1 (de) 1991-01-17
JPH0660105B2 (ja) 1994-08-10
NO163514B (no) 1990-03-05
EP0099445B2 (en) 1998-07-08
DK164537C (da) 1992-11-30
AU1346283A (en) 1983-10-20
CA1207229A (en) 1986-07-08
EP0099445A3 (en) 1985-01-16
AU561900B2 (en) 1987-05-21
NZ203878A (en) 1986-02-21
NO831304L (no) 1983-10-17
FI831146L (fi) 1983-10-15

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